Human health is dependent upon the structure and integrity of the epidermis which functions as a barrier between the environment and the organism. Intercellular contacts in the epidermis are important in maintaining epidermal integrity for the skin cannot fulfill its selective barrier function unless cell adhesive mechanisms operate efficiently and effectively. There is strong in vitro evidence that calcium-dependent adhesion molecules, E- and P-cadherin, are required for normal intercellular adhesion in the epidermis. Additional in vitro data suggests that the cadherins are also involved in regulation of epidermal morphogenesis. The goal of this proposal is to test the hypothesis that cadherins mediate normal keratinocyte stratification and differentiation using an in vivo mouse model. The focus will be the generation of a strain of transgenic mice in which cadherin function is eliminated from the suprabasal layers of epidermis by expressing a dominant negative cadherin under the control of the human keratin 1 promoter, which selectively targets the suprabasal layers of the epidermis. A combination of biochemical, molecular and histological techniques will be used to characterize the phenotype of the epidermis expressing the dominant negative cadherin. Loss of cadherin function in the suprabasal compartment of the epidermis is predicted to severely compromise cell-cell adhesion in the epidermis, thereby leading to defective structural organization and integrity. Furthermore, the loss of cadherin-mediated adhesive signals is predicted to affect epidermal differentiation, with some markers expressed premataturely and others greatly inhibited. These studies will rigourously test the involvement of cadherins in the development and maintenance of normal epidermal integrity and function.